Background: While there is considerable literature on adults with Down syndrome who have dementia, there is little published on the epidemiology of other types of mental ill-health in this population. Method: Longitudinal cohort study of adults with Down syndrome who received detailed psychiatric assessment (n = 186 at the first time point; n = 134 at the second time point, 2 years later). Results: The prevalence of Down syndrome for the 16 years and over population was 5.9 per 10 000 general population. Point prevalence of mental ill-health of any type, excluding specific phobias, was 23.7% by clinical, 19.9% by Diagnostic Criteria for Psychiatric Disorders for use with Adults with Learning Disabilities/Mental Retardation (DC-LD), 11.3% by ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research (DCR-ICD-10) and 10.8% by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Revised (DSM-IV-TR) criteria. Two-year incidence of mental ill-health of any type was 14.9% by clinical and DC-LD, 9.0% by DCR-ICD-10 and 3.7% by DSM-IV-TR criteria. The highest incidence was for depressive episode (5.2%) and dementia/delirium (5.2%). Compared with persons with intellectual disabilities (ID) of all causes, the standardized rate for prevalence of mental ill-health was 0.6 (0.4-0.8), or 0.4 (0.3-0.6) if organic disorders are excluded, and the standardized incidence ratio for mental ill-health was 0.9 (0.6-1.4), or 0.7 (0.4-1.2) if organic disorders are excluded. Urinary incontinence was independently associated with mental ill-health, whereas other personal factors, lifestyle and supports, and other types of health needs and disabilities were not. Conclusions: Mental ill-health is less prevalent in adults with Down syndrome than for other adults with ID. The pattern of associated factors differs from that is found for other adults with ID, with few associations found. This suggests that the protection against mental ill-health isbiologically determined in this population, or that there are other factors protective for mental ill-health yet to be identified for the population with Down syndrome.